Tissue fibrosis is the major cause for disability and death related to a variety of diseases worldwide. According to relevant statistics, 45% of patients who died from various diseases in the United States can be attributed to tissue fibrosis hyperplasia-related diseases. The body organs are composed of two parts: parenchyma refers to the main structure and functional cells of organs (for example, hepatic parenchyma cell is hepatocyte), and mesenchyme consists of stromal cell and extracellular matrix (mainly have collagen, proteoglycan, saccharide, glycoprotein and elastin) which distributes between parenchymal cells and is mainly for mechanical support and connection. In addition, the extracellular matrix can constitute a microenvironment that maintains the physiological activities of cells, is a bridge for signal transduction, participates in a variety of physiological and pathological processes, and plays an important role in tissue repair and fibrosis. Damage caused by any cause can cause degeneration and death of tissue cells, and inflammation. If the damage is less, the normal parenchymal cells surrounding the damaged cells will proliferate and repair the damaged tissue, and this repair can be completely restored to normal structure and function. However, if the damage is larger or repeated damage, and exceeds the regenerative capacity of the surrounding parenchymal cells, the interstitial fibrous connective tissue (extracellular matrix) will proliferate massively to repair the defect tissue, that is, pathological changes of fibrosis occur. Therefore, fibrosis is essentially a repair response to tissue damage to protect the relative integrity of tissues and organs. Although the proliferating fibrous connective tissue repairs the defect, it does not have the structure and function of the original organ parenchymal cells. If this repair is overreacted, too strong and out of control, it will lead to fibrosis of organs and cause a decline of organ functions. Thus, fibrosis refers to the pathological process in which the parenchymal cells are necrotic due to inflammation, and the extracellular matrix in the tissue is abnormally increased and excessively deposited. The light one becomes fibrosis, and the severe one causes the destruction of the tissue structure and then the organ hardens. Among various fibrosis-related diseases, pulmonary fibrosis and liver fibrosis are the most common.
Idiopathic Pulmonary Fibrosis (IPF) is a typical chronic, progressive and fatal fibrotic interstitial pneumonia characterized by progressive dyspnea and a gradual decline in lung function, which quickly leads to respiratory failure and death. At least 5 million people worldwide suffered from this in 2008, 130,000 to 500,000 people only in the United States in 2010. About 48,000 new cases were reported and about 40,000 people died of IPF each year. The incidence of IPF is estimated to be 4.6-7.4/100,000, and 30,000 to 35,000 new cases are diagnosed each year. The incidence of smokers is much greater than that of non-smokers. The incidence of IPF can reach nearly 2.3% in people with a smoke history of 20-40 years. The incidence of males is higher than that of females. The 5-year individual survival rate of IPF is about 20%, and the mortality rate is much higher than that of many cancers, which is known as a cancer that is not cancer actually. Potential risk factors include occupational exposure and environmental pollution such as metals, animals, wood chips, smoking and smog.
The pathogenesis of IPF is complex and is generally thought to involve interactions between pro-inflammatory and pro-fibrotic pathways, but the exact mechanism is still unknown. In 2014, Roche's Pirfenidone and Boehringer Ingelheim's nintedanib were first approved in the United States, and annual sales peak of Pirfenidone is estimated to reach $2 billion in 2019. The prognosis of IPF is poor at present, and treatment solutions are scarce. The marketing of these two new drugs gives confidence in the progression of IPF disease, and these two drugs are likely to be used to treat other fibrotic diseases. However, the development of novel IPF drugs gets continuously valued since there are still unsatisfied clinical demands for large quantity of patients.